WO2006133242A2 - Inhibiteurs d'azinone et de diazinone v3 utilises dans les troubles lies a la depression et au stress - Google Patents
Inhibiteurs d'azinone et de diazinone v3 utilises dans les troubles lies a la depression et au stress Download PDFInfo
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- WO2006133242A2 WO2006133242A2 PCT/US2006/022025 US2006022025W WO2006133242A2 WO 2006133242 A2 WO2006133242 A2 WO 2006133242A2 US 2006022025 W US2006022025 W US 2006022025W WO 2006133242 A2 WO2006133242 A2 WO 2006133242A2
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- 0 **N1N=CC([Al])=C(CC(NI)=O)C1=O Chemical compound **N1N=CC([Al])=C(CC(NI)=O)C1=O 0.000 description 7
- SNIJCXFMZCPGOA-UHFFFAOYSA-N Bc1cc(OC)ccc1 Chemical compound Bc1cc(OC)ccc1 SNIJCXFMZCPGOA-UHFFFAOYSA-N 0.000 description 1
- BQYJNIRSHMTSFO-IWQZZHSRSA-N C1C/C=C\CCNCC1 Chemical compound C1C/C=C\CCNCC1 BQYJNIRSHMTSFO-IWQZZHSRSA-N 0.000 description 1
- WAOHQEWUNNDDLM-UHFFFAOYSA-N CC(C)(C)NC(CN(C(c1cc(OC)ccc1)=CC=C1/C(/N)=N/O)C1=O)=O Chemical compound CC(C)(C)NC(CN(C(c1cc(OC)ccc1)=CC=C1/C(/N)=N/O)C1=O)=O WAOHQEWUNNDDLM-UHFFFAOYSA-N 0.000 description 1
- SRXLJLRKLRMRBS-UHFFFAOYSA-N CC(C)(C)NC(CN(C(c1cc(OC)ccc1)=CC=C1c2n[o]c(CCN3CCCCC3)n2)C1=O)=O Chemical compound CC(C)(C)NC(CN(C(c1cc(OC)ccc1)=CC=C1c2n[o]c(CCN3CCCCC3)n2)C1=O)=O SRXLJLRKLRMRBS-UHFFFAOYSA-N 0.000 description 1
- HTLFOTVOXOVNPI-UHFFFAOYSA-N CC(C)NC(CN(C(C(C1)=CC=CC1(C)OC)=CC=C1c2n[o]c(CCN3CCCCC3)n2)C1=O)=O Chemical compound CC(C)NC(CN(C(C(C1)=CC=CC1(C)OC)=CC=C1c2n[o]c(CCN3CCCCC3)n2)C1=O)=O HTLFOTVOXOVNPI-UHFFFAOYSA-N 0.000 description 1
- AVADUTYHDQDELJ-UHFFFAOYSA-N CC(C)NC(CN(C(c1cc(OC)ccc1)=CN=C1N2CCC(CCN(C)C)CC2)C1=O)=O Chemical compound CC(C)NC(CN(C(c1cc(OC)ccc1)=CN=C1N2CCC(CCN(C)C)CC2)C1=O)=O AVADUTYHDQDELJ-UHFFFAOYSA-N 0.000 description 1
- AMEVLDGDEHIATO-UHFFFAOYSA-N CC(C)NC(CN(C(c1ccccc1)=CC=C1C(NCCCN2CCCCC2)=O)C1=O)=O Chemical compound CC(C)NC(CN(C(c1ccccc1)=CC=C1C(NCCCN2CCCCC2)=O)C1=O)=O AMEVLDGDEHIATO-UHFFFAOYSA-N 0.000 description 1
- UMGGSCTUGARCPV-UHFFFAOYSA-N CC(C)NC(CN(C(c1ccccc1)=CC=C1C(NCCc2ccccn2)=O)C1=O)=O Chemical compound CC(C)NC(CN(C(c1ccccc1)=CC=C1C(NCCc2ccccn2)=O)C1=O)=O UMGGSCTUGARCPV-UHFFFAOYSA-N 0.000 description 1
- YJIWZPQVVAJSNC-UHFFFAOYSA-N CC(C)NC(CN1C(c2cc(Cl)ccc2)=NCC(C2OC2NCCCN2CCCCC2)C1=O)=O Chemical compound CC(C)NC(CN1C(c2cc(Cl)ccc2)=NCC(C2OC2NCCCN2CCCCC2)C1=O)=O YJIWZPQVVAJSNC-UHFFFAOYSA-N 0.000 description 1
- PFCDIBCJSSKADD-UHFFFAOYSA-N CC(C)NC(Cc(cc(cc1)-c2cccc(O)c2)c1-c1cc(OC)ccc1)=O Chemical compound CC(C)NC(Cc(cc(cc1)-c2cccc(O)c2)c1-c1cc(OC)ccc1)=O PFCDIBCJSSKADD-UHFFFAOYSA-N 0.000 description 1
- DIZQNUOTSJPNMY-UHFFFAOYSA-N CC(C)NC(Cc(cc(cc1)-c2cccc(OCCCN3CCCCC3)c2)c1-c1cc(OC)ccc1)=O Chemical compound CC(C)NC(Cc(cc(cc1)-c2cccc(OCCCN3CCCCC3)c2)c1-c1cc(OC)ccc1)=O DIZQNUOTSJPNMY-UHFFFAOYSA-N 0.000 description 1
- DDDJLTPULPOBRG-UHFFFAOYSA-N CC(C)NC(Cc(cc(cc1)O)c1-c1cc(OC)ccc1)=O Chemical compound CC(C)NC(Cc(cc(cc1)O)c1-c1cc(OC)ccc1)=O DDDJLTPULPOBRG-UHFFFAOYSA-N 0.000 description 1
- MPRASCUUHIQYFQ-UHFFFAOYSA-N CC(CCc1ccccc1)Cl Chemical compound CC(CCc1ccccc1)Cl MPRASCUUHIQYFQ-UHFFFAOYSA-N 0.000 description 1
- ULTVUHBYBVMXJF-UHFFFAOYSA-N CCOC(C(C(OCC)=O)c1c(-c2ccccc2)c(Cl)nc(-c2cccc(OCc3ccccc3)c2)n1)=O Chemical compound CCOC(C(C(OCC)=O)c1c(-c2ccccc2)c(Cl)nc(-c2cccc(OCc3ccccc3)c2)n1)=O ULTVUHBYBVMXJF-UHFFFAOYSA-N 0.000 description 1
- FGYDHYCFHBSNPE-UHFFFAOYSA-N CCOC(C(C(OCC)=O)c1ccccc1)=O Chemical compound CCOC(C(C(OCC)=O)c1ccccc1)=O FGYDHYCFHBSNPE-UHFFFAOYSA-N 0.000 description 1
- MPAWVDTVWPPKJQ-UHFFFAOYSA-N CCOC(CCN1CCCCC1)=O Chemical compound CCOC(CCN1CCCCC1)=O MPAWVDTVWPPKJQ-UHFFFAOYSA-N 0.000 description 1
- UWCMKRXGRNQOCI-UHFFFAOYSA-N CNC(c1cc(OCc2ccccc2)ccc1)=N Chemical compound CNC(c1cc(OCc2ccccc2)ccc1)=N UWCMKRXGRNQOCI-UHFFFAOYSA-N 0.000 description 1
- ISSUFFKMWHZACJ-UHFFFAOYSA-N Clc1nc(-c2cccc(OCc3ccccc3)c2)nc(Cl)c1-c1ccccc1 Chemical compound Clc1nc(-c2cccc(OCc3ccccc3)c2)nc(Cl)c1-c1ccccc1 ISSUFFKMWHZACJ-UHFFFAOYSA-N 0.000 description 1
- UXYDJDLVMMJKHF-UHFFFAOYSA-N NC(c1cccc(OCc2ccccc2)c1)=N Chemical compound NC(c1cccc(OCc2ccccc2)c1)=N UXYDJDLVMMJKHF-UHFFFAOYSA-N 0.000 description 1
- KNYZPKZWICBMPT-UHFFFAOYSA-N O=C(C1c2ccccc2)NC(c2cccc(OCc3ccccc3)c2)NC1=O Chemical compound O=C(C1c2ccccc2)NC(c2cccc(OCc3ccccc3)c2)NC1=O KNYZPKZWICBMPT-UHFFFAOYSA-N 0.000 description 1
- TXYRRPKNROMYEC-UHFFFAOYSA-N OC(Cc1c(-c2ccccc2)c(Cl)nc(-c2cccc(OCc3ccccc3)c2)n1)=O Chemical compound OC(Cc1c(-c2ccccc2)c(Cl)nc(-c2cccc(OCc3ccccc3)c2)n1)=O TXYRRPKNROMYEC-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
- A61P5/46—Drugs for disorders of the endocrine system of the suprarenal hormones for decreasing, blocking or antagonising the activity of glucocorticosteroids
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
- C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
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- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Definitions
- the invention relates to a chemical class of substituted pyridines, pyrimidines, pyrazines, pyridinones, pyrimidinones, pyrazinones and phenylacetamides useful in treating depression, stress and other disorders.
- hypothalamo-pituitary-adrenal (HPA) axis is the major stress axis in humans and other mammals.
- a variety of stressors and multiple other classes of stimuli) cause release of the hormone ACTH (adrenocorticotropic hormone) from the anterior pituitary gland.
- ACTH enters the systemic circulation and acts on the adrenal cortex to promote synthesis and release of glucocorticoid hormone (the major endogenous glucocorticoid being Cortisol in humans and corticosterone in rodents).
- the glucocorticoids exert a broad spectrum of effects, the main purpose of which is to mobilize energy sources for successful responsiveness and eventual adaptation to the stressor.
- dysregulation of the HPA axis is a reflection of enhanced vulnerability and poor adaptation to chronic stress and that chronic stress therefore plays a major role in the development of affective illness (Sperry and Carlson, DSM-IV diagnosis to treatment, 2 nd Edition, Taylor & Francis, 1996).
- This central concept is supported by experimental evidence utilizing animal models of chronic stress, where aberrant HPA function closely resembles that seen in clinical settings (De Goeij et al, Neuroendocrinology, 1991, 53, 150-159; Plotsky and Meaney, MoI. Brain Res. 1993, 18, 195-200).
- CRH corticotropin releasing hormone
- AVP arginine vasopressin
- the HPA axis is most potently activated by psychological stressors ⁇ i.e., those which require a cognitive assessment of the stimulus).
- the patterns of AVP and CRH release vary as a function of the type of stressor involved. Acute stress, whether physical or psychological, elicits rapid and robust CRH release. For several psychological stressors, however, chronic application elicits enhanced AVP storage in the median eminence, increased niRNA synthesis, and reduction in AVP neurosecretory granules, whereas similar markers of CRH synthesis and release are relatively unaffected.
- V3 antagonists may be useful in the treatment of aggressive behavior [see Wersinger et al. MoI. Psychiatry 7. 975- 984 (2002); Blanchard et al. Pharmcol. Biochem. Behav. 80. 189-194 (2005); and Wersinger et al. Horm. Behav. 46, 638-645 (2004)]; insomnia in elderly patients [see Kalamatianos et al. J. Neuroendocrinol. 16, 493-501 (2004)]; cancer [see Dahia et al. J. Clin. Endocrin. Metab. 81. 1768-1771 (1996)]; Cushing's Disease [see Perraudin et al. J. Clin. Endocrin.
- vasopressin In addition to the V3 receptor, vasopressin also activates peripheral receptors, i.e., the Via receptor, predominantly found on liver and vascular tissue and the V2 receptor, predominantly found on kidney tissue. Interaction at these receptors mediates the pressor and antidiuretic actions of AVP.
- peripheral receptors i.e., the Via receptor
- the Via receptor predominantly found on liver and vascular tissue
- the V2 receptor predominantly found on kidney tissue. Interaction at these receptors mediates the pressor and antidiuretic actions of AVP.
- X 4 -X 5 is chosen from CR 4 -CR 5 , N-CR 5 and CR 4 -N; in genus in, one of X 6 , X 7 and X 8 is N and the other two are CR 4 and CR 5 .
- R 1 is chosen from (C 1- io)alkyl, (Cs. ⁇ cycloalkyl, [(C 3-1 o)cycloalkyl(Ci -2 )alkyl], said (C 1-1 o)alkyl, (C 3-1 o)cycloalkyl, and [(C 3-10 )cycloalkyl (C 1-2 )alkyl] being optionally substituted with one or more halogens, (Q ⁇ alkoxy, (C 2- 6 )alkenyl, (C 2-6 )alkynyl, phenyl or benzyl; Ar is chosen from (C 1- io)alkyl, (Cs. ⁇ cycloalkyl, [(C 3-1 o)cycloalkyl(Ci -2 )alkyl], said (C 1-1 o)alkyl, (C 3-1 o)cycloalkyl, and [(C 3-10 )cycloalkyl (C 1-2 )alkyl] being optionally
- R 4 and R 5 are independently chosen from H, (Ci -6 )alkyl, (Ci ⁇ alkyloxy or halogen, said (Ci ⁇ alkyl and (Ci ⁇ alkyloxy being optionally substituted with one or more halogens;
- G is a linking moiety spanning 4 to 7 atoms between termini; and R 8 and R 9 are residues that, in combination, maintain the basicity of N.
- R 1 When X ⁇ -X 5 is CR 4 -N and G is alkylene, R 1 must be chosen from (Ci -6 )alkyl, (C 3-6 )cycloalkyl and [(C 3-6 )cycloalkyl(Ci -2 )alkyl].
- R 1 is not restricted to this subset of values, G is a linking moiety incorporating at least one of (a) an sp2 hybridized carbon; or (b) a cyclic structure.
- G may additionally be -N(R 10 )-(C 4-6 )alkylene for all values of R 1 .
- R 10 is H or (C 1-6 )alkyl.
- a subgenus of compounds in accordance with embodiments of the invention is the genus I:
- the genus I can be divided into three subgenera:
- compositions comprising a pharmaceutically acceptable carrier and a compound as described above.
- pyridines pyrimidines, pyrazines, pyridinones, pyrimidinones, pyrazinones and phenylacetamides falling within a general formula
- B represents a six-membered, planar carbocycle or planar nitrogen heterocycle.
- G is a linking moiety spanning 4 to 7 atoms between termini.
- the -NR 8 R 9 must be 4 to 7 atoms removed from the ring B.
- the precise constituents of G are not critical.
- G will incorporate either an sp2 hybridized carbon or a cyclic structure.
- R 8 and R 9 together form a 4- to 7-menibered nitrogenous heterocycle, G may be -N(R 10 )-(C 4 . 6 )alkylene.
- G may also be an optionally substituted carbocycle or heterocycle, attached to the B ring and to -NR 8 R 9 by a direct bond or by a C 1 -C 5 alkylene chain.
- G may also be an optionally substituted nitrogenous heterocycle, attached to the B ring by a direct bond or by a C 1 -C 5 alkylene chain; in this case a nitrogen of the nitrogenous heterocycle may correspond to -NR 8 R 9 so that R 9 becomes formally part of G.
- R and R may also be taken together and attach to G so as to form a nitrogen-containing heterocycle, e.g. a pyridine ring attached at one of the ring carbon atoms to the linker which links the pyridine ring to ring B. In such cases, there will be 4 to 7 atoms between the ring B and the carbon atom of the nitrogen-containing heterocycle.
- the residues R 8 and R 9 must maintain the basicity of N.
- alkyl residues of various sorts are within the invention; alkylene and similar residues (e.g. alkylene with heteroatom interruption) that tie the nitrogen into a ring are within the invention. Even residues that introduce aromaticity are tolerated, as long as the nitrogen remains basic (e.g. pyridine).
- R 8 and R 9 may be hydrogen.
- a genus in accordance with some embodiments of the invention comprises pyridinones, pyrimidinones and pyrazinones that fall within the general formula I above:
- X 5 is CR 4 -CR 5 , N-CR 5 or CR 4 -N.
- subgenera in accordance with embodiments of the invention include the subgenus in which -NR 8 R 9 is a saturated nitrogenous heterocycle of 3 to 10 carbons in one or two rings, preferably a piperidine or morpholine, and G is a (Cs. ⁇ hydrocarbon chain attached to the pyridinone, pyrimidinone or pyrazinone through an amide or amine:
- E is (C 2-1 o)hydrocarbon; and — is a saturated nitrogenous heterocycle of 3 to 10 carbons in one or two rings.
- the nitrogenous heterocycle may be substituted, for example, 4-hydroxypiperidin-l-yl, 4-hydroxy-4- methylpiperidin-1-yl and 4,4-dimethylpiperidin-l-yl.
- the (C 2- io)hydrocarbon may be straight chain, branched or cyclic as long as the 4-7 atom spacing between -NR 8 R 9 and the pyridinone, pyrimidinone or pyrazinone ring is maintained. Examples of species in this subgenus include:
- a further example of a subgenus in accordance with embodiments of the invention is the subgenus in which -NR 8 R 9 is attached via a direct bond or (Ci- 6 )hydrocarbon, J, to a single ring carbocycle or heterocycle of 4 to 7 atoms or a
- the carbocycle or heterocycle is directly attached to the pyridinone, pyrimidinone or pyrazinone:
- nitrogenous heterocycle e.g. oxadiazolyl, pyrrolidinyl and piperidinyl
- J is methylene, ethylene or propylene
- -NR 8 R 9 is chosen from piperidine, morpholine and -N[C 1-3 alkyl] 2 .
- species in this subgenus include:
- a further example of a subgenus in accordance with embodiments of the invention is the subgenus in which R is alkylene or similar residue (e.g. alkylene with heteroatom interruption) "tied back" into a nitrogen that is directly attached to the pyridinone, pyrimidinone or pyrazinone ring:
- hexahydro-l,4-diazepine ring is a hexahydro-l,4-diazepine ring.
- An example is
- a further example of a subgenus in accordance with embodiments of the invention is the subgenus in which R 9 is alkylene or similar residue (e.g. alkylene with heteroatom interruption) "tied back" into a chain that is attached to the pyridinone, pyrimidinone or pyrazinone ring through an amine or amide linkage.
- R 9 is alkylene or similar residue (e.g. alkylene with heteroatom interruption) "tied back" into a chain that is attached to the pyridinone, pyrimidinone or pyrazinone ring through an amine or amide linkage.
- R 8 is C 1-10 hydrocarbon.
- This particular subgenus also includes compounds of the formulae in which R 1 is C 3 -C 6 alkyl.
- R 1 is C 3 -C 6 alkyl.
- R 8 and R may be taken together and attach to G so as to form a nitrogen-containing heterocycle.
- Pyr represents imidazole, pyridine attached through a carbon, substituted imidazole or substituted pyridine attached through a carbon.
- An example is:
- R 1 may be chosen from C 3-6 alkyl and cycloalkyl and Ci -3 alkyl substituted with phenyl, methoxy or alkynyl.
- R 1 may be t-butyl, isopropyl, cyclopentyl, ⁇ -methylbenzyl, methoxypropyl or propargyl.
- Ar may be chosen from phenyl and phenyl substituted with halogen (e.g. chloro and fluoro), Ci -2 alkyl, (e.g. methyl) trifluoromethyl, C 1-3 alkyloxy (e.g. methoxy), C 1-4 cycloalkyloxy or trifluoromethoxy.
- Ar is a 3-substituted phenyl ring, for example a substituted phenyl ring selected from 3-chlorophenyl, 3- fiuorophenyl, 3-methoxyphenyl, 3-trifluoromethoxyphenyl, 3-chloro-4- fluorophenyl, 4-fluoro-3-methoxyphenyl and 3,5-dimethoxyphenyl.
- the compounds in accordance with embodiments of the invention all contain a basic nitrogen, they may be presented as salts.
- reference to the compound includes its salts.
- pharmaceutically acceptable salt refers to salts whose counter ion derives from pharmaceutically acceptable non-toxic acids and bases.
- Suitable pharmaceutically acceptable base addition salts for the compounds of the present invention include inorganic acids, and organic acids.
- Examples include acetate, benzenesulfonate (besylate), benzoate, bicarbonate, bisulfate, carbonate, camphorsulfonate, citrate, ethanesulfonate, fumarate, gluconate, glutamate, glycolate, bromide, chloride, isethionate, lactate, maleate, malate, mandelate, methanesulfonate, mucate, nitrate, pamoate, pantothenate, phosphate, succinate, sulfate, tartrate, trifluoroacetate, p-toluenesulfonate, acetamidobenzoate, adipate, alginate, aminosalicylate, anhydromethylenecitrate, ascorbate, aspartate, calcium edetate, camphorate, camsylate, caprate, caproate, caprylate, cinnamate, cyclamate, dichloroacetate, ede
- suitable pharmaceutically acceptable base addition salts for the compounds of the present invention include ammonium, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N 5 N'- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
- base addition salts includes those made from: arecoline, arginine, barium, benethamine, benzathine, betaine, bismuth, clemizole, copper, deanol, diethylamine, diethylaminoethanol, epolamine, ethylenediamine, ferric, ferrous, glucamine, glucosamine, histidine, hydrabamine, imidazole, isopropylamine, manganic, manganous, methylglucamine, morpholine, morpholineethanol, n- ethylmorpholine, n-ethylpiperidine, piperazine, piperidine, polyamine resins, purines, theobromine, triethylamine, trimethylamine, tripropylamine, trolamine, and tromethamine.
- Alkyl is intended to include linear, branched, or cyclic hydrocarbon structures and combinations thereof. When not otherwise restricted, the term refers to alkyl of 20 or fewer carbons. Lower alkyl refers to alkyl groups of 1-6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s-and t-butyl and the like. Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups of 3-8 carbon atoms. Examples of cycloalkyl groups include c-propyl, c-butyl, c-pentyl, norbornyl, adamantyl and the like. In accordance with standard nomenclature, the term "alkylene” applies to alkyl residues having two points of attachment. For example, propylene refers to -CH 2 CH 2 CH 2 -.
- hydrocarbon includes alkyl, cycloalkyl, alkenyl, alkynyl, aryl and combinations thereof. Examples include benzyl, phenethyl, cyclohexylmethyl, camphoryl and naphthylethyl.
- Alkoxy or alkoxyl refers to groups of 1-8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower-alkoxy refers to groups containing one to four carbons.
- Oxaalkyl refers to alkyl residues in which one or more carbons (and their associated hydrogens) have been replaced by oxygen. Examples include methoxypropoxy, 3,6,9-trioxadecyl and the like.
- the term oxaalkyl is intended as it is understood in the art [see Naming and Indexing of Chemical Substances for Chemical Abstracts, published by the American Chemical Society, ⁇ fI 96, but without the restriction of Tfl27(a)], i.e. it refers to compounds in which the oxygen is bonded via a single bond to its adjacent atoms (forming ether bonds).
- thiaalkyl and azaalkyl refer to alkyl residues in which one or more carbons have been replaced by sulfur or nitrogen, respectively. Examples include ethylaminoethyl and methylthiopropyl.
- Acyl refers to groups of 1-8 carbon atoms of a straight, branched, cyclic configuration, saturated, unsaturated and aromatic and combinations thereof, attached to the parent structure through a carbonyl functionality.
- One or more carbons in the acyl residue may be replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent remains at the carbonyl. Examples include formyl, acetyl, propionyl, isobutyryl, ⁇ -butoxycarbonyl, benzoyl, benzyloxycarbonyl and the like.
- Lower-acyl refers to groups containing one to four carbons.
- Aryl and heteroaryl refer to aromatic or heteroaromatic rings, respectively, as substituents.
- Heteroaryl contains one, two or three heteroatoms selected from O, N, or S. Both refer to monocyclic 5- or 6-membered aromatic or heteroaromatic rings, bicyclic 9- or 10-membered aromatic or heteroaromatic rings and tricyclic 13- or 14-membered aromatic or heteroaromatic rings.
- Aromatic 6-14-membered carbocyclic rings include, e.g., benzene, naphthalene, indane, tetralin, and fluorene and the 5-10-membered aromatic heterocyclic rings include, e.g., imidazole, pyridine, indole, thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole.
- Arylalkyl means an alkyl residue attached to an aryl ring. Examples are benzyl, phenethyl and the like.
- Substituted alkyl, aryl, cycloalkyl, heterocyclyl etc. refer to alkyl, aryl, cycloalkyl, or heterocyclyl wherein up to three H atoms in each residue are replaced with halogen, haloalkyl, hydroxy, loweralkoxy, carboxy, carboalkoxy (also referred to as alkoxycarbonyl), carboxamido (also referred to as alkylaminocarbonyl), cyano, carbonyl, nitro, amino, alkylamino, dialkylamino, mercapto, alkylthio, sulfoxide, sulfone, acylamino, amidino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, or heteroaryloxy.
- halogen means fluorine, chlorine, bromine or iodine.
- R-groups may form rings or heterocycles.
- R 8 and R 9 together form a 4- to 7-membered nitrogenous heterocycle. It is intended that these rings may exhibit various degrees of unsaturation, may include heteroatoms and may be substituted with lower alkyl or alkoxy.
- the compounds of this invention can exist in radiolabeled form, i.e., the compounds may contain one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
- Radioisotopes of hydrogen, carbon, phosphorous, fluorine, and chlorine include 3 H, 14 C, 35 S, 18 F, and 36 Cl, respectively.
- Compounds that contain those radioisotopes and/or other radioisotopes of other atoms are within the scope of embodiments of the invention. Tritiated, i.e. 3 H, and carbon-14, i.e., 14 C, radioisotopes are particularly known for their ease in preparation and detectability.
- Radiolabeled compounds of this invention can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabeled compounds can be prepared by carrying out the procedures disclosed in the Examples and Schemes by substituting a readily available radiolabeled reagent for a non-radiolabeled reagent. Radiolabeled compounds are useful in screens for V3 agonists and antagonists.
- the compounds described herein may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms.
- Each chiral center may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. Included in embodiments of the present invention are all such possible isomers, as well as their racemic and optically pure forms.
- Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
- the compounds described herein contain olefmic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.
- Me, Et, Ph, Tf, Ts and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, toluenesulfonyl and methanesulfonyl respectively.
- the following abbreviations and terms have the indicated meanings throughout:
- EDC, EDCI 1 -ethyl-3 -(3 '-dimethylaminopropyl)carbodiimide
- NMO N-methylmorpholine oxide
- Ph phenyl
- PPTS pyridinium p-toluenesulfonate
- a pharmaceutical composition comprising a compound as described herein or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically carriers thereof and optionally one or more other therapeutic ingredients.
- the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
- the formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration.
- the most suitable route may depend upon the condition and disorder of the recipient.
- the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods of treatment in accordance with embodiments of the invention include the step of bringing into association a compound in accordance with embodiments of the invention or a pharmaceutically acceptable salt or solvate thereof ("active ingredient”) with the carrier, which constitutes one or more accessory ingredients.
- active ingredient a compound in accordance with embodiments of the invention or a pharmaceutically acceptable salt or solvate thereof
- the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
- Formulations in accordance with embodiments of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in- water liquid emulsion or a water-in-oil liquid emulsion.
- the active ingredient may also be presented as a bolus, electuary or paste.
- a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
- Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent.
- Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
- the tablets may optionally be coated or scored and may be formulated so as to provide sustained, delayed or controlled release of the active ingredient therein.
- the pharmaceutical compositions may include a "pharmaceutically acceptable inert carrier", and this expression is intended to include one or more inert excipients, which include starches, polyols, granulating agents, macrocrystalline cellulose, diluents, lubricants, binders, disintegrating agents, and the like. If desired, tablet dosages of the disclosed compositions may be coated by standard aqueous or nonaqueous techniques, "Pharmaceutically acceptable carrier” also encompasses controlled release means.
- compositions in accordance with embodiments of the present invention may also optionally include other therapeutic ingredients, anti-caking agents, preservatives, sweetening agents, colorants, flavors, desiccants, plasticizers, dyes, and the like. Any such optional ingredient must, of course, be compatible with the compound of the invention to insure the stability of the formulation.
- the dose range for adult humans is generally from 0.005 mg to 10 g/day orally. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of a compound or mixture of compounds in accordance with embodiments of the invention which is or are effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.
- the precise amount of compound or compounds administered to a patient will be the responsibility of the attendant physician. However, the dose employed will depend on a number of factors, including the age and sex of the patient, the precise disorder being treated, and its severity.
- Carboxylic acid 3-2 was prepared from alkene 3-1 (159 mg; 0.378 mmol) using the general procedures analogous to those described in Example 2, Steps 3 and 4. This afforded 130 mg (78% for 2 steps from 3-1) of acid 3-2.
- Compound 7-1 was prepared from literature procedures (J. Med. Chem., 2003, 46, 4050-4062). To a solution of compound 7-1 (1.0 g, 2.4 mmol) in acetonitrile (25 mL) was added l-(2-(pyrrolidin-3-yl)ethyl)piperidine trifluoroacetic acid (666 mg, 2.4 mmol) and potassium carbonate (660 mg, 2.4 mmol). The mixture was stirred at reflux for 16 h. After cooling to rt, the mixture was filtered and the filtrate was concentrated. The filtrate was then diluted with CH 2 Cl 2 (3OmL) and washed with saturated brine solution.
- Compound 8-1 was prepared from similar procedures in Example 7. To a solution of 8-1 (90 mg, 0.17 mmol) in methanol (2 mL) was added 10% Pd/C (catalytic amount). The reaction was stirred under 1 arm of hydrogen for 16 h. The mixture was filtered and evaporated to afford 8-2 (70 mg, 0.16 mmol, 94%). Compound 8-2 was coupled with isopropylamine by using the same procedures in Example 7 to give 8-3. Data for 8-3: MS (ESI), m/z (assignment): 490/492 ([M+H] + , 100/35).
- Table 1 shows compounds that exhibited IC5 0 less than 10 ⁇ M:
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Abstract
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EP06760716.8A EP1890697B1 (fr) | 2005-06-07 | 2006-06-07 | Inhibiteurs d'azinone et de diazinone v3 utilises dans les troubles lies a la depression et au stress |
CN2006800237203A CN101212969B (zh) | 2005-06-07 | 2006-06-07 | 用于抑郁和应激障碍的嗪酮和二嗪酮v3抑制剂 |
CA002610400A CA2610400A1 (fr) | 2005-06-07 | 2006-06-07 | Inhibiteurs d'azinone et de diazinone v3 utilises dans les troubles lies a la depression et au stress |
BRPI0611348-6A BRPI0611348A2 (pt) | 2005-06-07 | 2006-06-07 | composto, formulação farmacêutica, método para realizar diurese ou tratamento de um distúrbio, e, uso de um composto |
MX2007015427A MX2007015427A (es) | 2005-06-07 | 2006-06-07 | Inhibidores de azinona y diazinona v3 para depresion y trastornos de estres. |
JP2008515847A JP5002592B2 (ja) | 2005-06-07 | 2006-06-07 | うつ病およびストレス疾患のためのアジノンおよびジアジノンv3阻害剤 |
IL187634A IL187634A0 (en) | 2005-06-07 | 2007-11-26 | Azinone and diazinone v3 inhibitors for depression and stress disorders |
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US (1) | US8350043B2 (fr) |
EP (1) | EP1890697B1 (fr) |
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WO2012043791A1 (fr) | 2010-10-01 | 2012-04-05 | 大正製薬株式会社 | Dérivé de 1,2,4-triazolone |
WO2012122171A1 (fr) | 2011-03-09 | 2012-09-13 | E. I. Du Pont De Nemours And Company | Oxohétérocycles bis-azotés herbicides |
WO2012148622A1 (fr) | 2011-04-28 | 2012-11-01 | E. I. Du Pont De Nemours And Company | Pyrazinones herbicides |
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EP2978425B1 (fr) | 2013-03-27 | 2017-09-27 | Merck Sharp & Dohme Corp. | Inhibiteurs du facteur xia |
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- 2006-06-07 JP JP2008515847A patent/JP5002592B2/ja not_active Expired - Fee Related
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Also Published As
Publication number | Publication date |
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EP1890697B1 (fr) | 2015-03-04 |
US8350043B2 (en) | 2013-01-08 |
MX2007015427A (es) | 2008-04-16 |
WO2006133242A3 (fr) | 2007-02-15 |
IL187634A0 (en) | 2008-03-20 |
CN101212969A (zh) | 2008-07-02 |
CA2610400A1 (fr) | 2006-12-14 |
JP5002592B2 (ja) | 2012-08-15 |
CN101212969B (zh) | 2013-08-07 |
AU2006255009A1 (en) | 2006-12-14 |
BRPI0611348A2 (pt) | 2010-12-07 |
EP1890697A2 (fr) | 2008-02-27 |
JP2008542444A (ja) | 2008-11-27 |
US20070037822A1 (en) | 2007-02-15 |
AU2006255009B2 (en) | 2011-10-27 |
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